PROJECT SUMMARY Squamous cell carcinoma of the oropharynx (SCCOP) is a highly morbid, life-threatening disease. Despite declining smoking prevalence, the incidence of SCCOP is increasing, particularly among younger adults. This trend is the result of the rising prevalence of oncogenic human papillomavirus (HPV) infection in the population. The majority (approximately 70-80%) of SCCOP patients are HPV-positive [HPV(+)]. HPV(+) SCCOP is distinct from HPV-negative [HPV(-)] SCCOP in terms of epidemiologic, clinical, and molecular features, and especially in terms of clinical behavior, response to treatment and survival. Therefore, in patients with SCCOP, determination of HPV status is critical for defining prognosis and tailoring therapy. Unfortunately, there is currently no effective screening method to identify patients with tumor HPV(+) SCCOP. Further, among patients with HPV(+) SCCOP, there remains heterogeneity in clinical outcomes. Identification of patients with SCCOP needing treatment intensification and those able to benefit from reduction of treatment intensity is critical to more effective and less morbid treatment. Noncoding RNAs (ncRNAs) that affect the immuno-inflammatory response control HPV clearance and escape of immune surveillance, and may contribute to tumor HPV status and related clinical outcomes of SCCOP patients. NcRNAs exhibit stable expression in human serum. We hypothesize that pretreatment serum expression profiles of immuno-inflammatory response ncRNAs are associated with tumor HPV(+) SCCOP and related clinical outcomes. The specific aims for this project are as follows: Aim 1: To determine if pretreatment serum expression profiles of selected immuno-inflammatory response ncRNAs are markers of tumor HPV status in a cohort of 1500 patients with incident SCCOP recruited, treated, and followed at The University of Texas MD Anderson Cancer Center. Aim 2: To determine if pretreatment serum expression profiles of selected immuno-inflammatory response ncRNAs predict disease-specific survival, disease-free survival, and overall survival among HPV(+) SCCOP patients from the cohort described for Aim 1. Aim 3: To validate significant associations found in Aims 1 and 2. We will use an independent cohort of 625 SCCOP cases to control for potential false-positive or unbiased estimates of associations. Aim 4: To characterize functions of immuno-inflammatory response ncRNAs on tumor radiosensitivity in vitro. We will screen a panel of HPV(+) SCCOP cell lines for ncRNAs of interest in a clinical setting, in order to further validate these prognostic ncRNAs found in Aim 2. This functional study will validate 1 or more of these ncRNAs as biomarkers that can be incorporated into prognostic prediction models to permit more personalized treatment. Identifying novel biomarkers for tumor HPV status and prognosis of patients with HPV(+) SCCOP will allow physicians to more effectively tailor screening for patients at risk of HPV(+) SCCOP, as well as treatment, and surveillance strategies that optimize survival and quality of life for patients with HPV(+) SCCOP.